Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][CH:14]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=1)[CH2:15][C:16]([OH:18])=[O:17].C(=O)([O-])[O-:29].[K+].[K+]>CS(C)=O.O>[CH3:13][CH:14]([CH2:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([N:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11]2)=[CH:23][CH:22]=1)[CH2:15][C:16]([OH:18])=[O:17]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(CCc1ccc(Cl)cc1)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(CC(=O)O)CC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 160 °C

Procedure:
A stirred mixture of 4-phenylpiperidine (0.161 g, 1.00 mmol), (±)3-methyl-5-(4-chloro-phenyl)-pentanoic acid (0.241 g, 1.00 mol), and potassium carbonate (0.276 g, 2.00 mol) in dry dimethyl sulfoxide was heated in a sand bath (160° C.) under nitrogen for 15 hours. The mixture was cooled and diluted with water. The aqueous solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to pH=6. A brown gum formed. The liquid was decanted, and the residue was chromatographed on silica gel (38 g, 230-400 mesh) eluting with dichloromethane-methanol (20:1, 15×40 mL). Fractions containing product were combined and rotary evaporated to give a brown glass. The glass was crystallized from methanol after a hot gravity filtration to give the title compound as a tan solid; yield 0.0360 g (10%, mp=134-135° C.).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH:15]=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:17]([C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2)(=O)[CH3:18].CO[Na].CO>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[C:15](=[O:16])[CH:18]=[CH:17][C:20]2[C:33]4[C:28]([CH:27]=[C:26]5[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1c2ccccc2cc2ccccc12
Reactant: CC(=O)c1c2ccccc2cc2ccccc12
Agent: CO[Na]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(C=Cc1c2ccccc2cc2ccccc12)c1c2ccccc2cc2ccccc12
Reaction time: 8 h
Yield: 91.3 %

Procedure:
9-anthraldehyde (10 mmol, 2.06 g) and 9-acetylanthracene (10 mmol, 2.2 g) were combined in dry DMF under N2 and MeONa (28 mmol, 1.5 g) was added. The reaction mixture is stirred overnight. Then MeOH was added (60 mL) and the precipitate was filtered off and vacuum dried to afford 3.73 g of pure 1,3-di(anthracene-9-yl)-2-propene-1-one. Portion of it (2.5 mmol, 1 g) was suspended in a mixture of dioxane and MeOH (60 mL and 20 mL respectively) and heated to 75° C. at which point sodium borohydride (5.3 mmol, 200 mg) was added. The mixture was stirred for 5 min and 50 mL of water was added. After the mixture had cooled to ambient, the solids were filtered off, washed with water and vacuum dried affording 620 mg of the title product.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.C1C2C(=O)CCCCC=2C=CN=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[CH:9][C:8]=4[C:2]3=[N:37]2)=[CH:32][CH:31]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CCCc2ccncc2C1=O
Agent: O=C1CCCCc2ccncc21
Product: O=C1CC2CCCc3ccncc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from 9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-8-acetic acid (prepared by hydrolysis of the corresponding ketal, the latter being prepared from 5,6,7,8-tetrahydrocyclohepta[c]pyridine-9-one (Hicks et al, J. Chem. Soc. Perkin I (1984)2297) according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]=1[C:10]([O:12]C)=[O:11])=[O:4].[OH-].[K+]>COCCOCCO>[C:3]([C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]=1[C:10]([OH:12])=[O:11])([OH:4])=[O:2]
Reactant: COC(=O)c1c(-c2ccccc2)cn(-c2ccccc2OC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCO
Product: COc1ccccc1-n1cc(-c2ccccc2)c(C(=O)O)c1C(=O)O
Yield: 61.9 %

Procedure:
A solution of 8,4 g of 2,3-di(methoxycarbonyl)-1-(2-methoxyphenyl)-4-phenyl-pyrrole and 2.6 g of KOH in diethyleneglycol monomethylether is refluxed for 3 hours. After cooling it is poured onto water, acidified and extracted 3 times with diethylether. The combined organic phases are washed with water, dried and evaporated down. The crude product is crystallised from diethylether. 4,8 g of 2,3-dicarboxy-1-(2-methoxyphenyl)-4-phenyl-pyrrole are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].BrCC(OC)=[O:20].C(OCC)(=O)C.[O:29]1C[CH2:32][CH2:31][CH2:30]1>O>[CH3:32][C:31]([CH2:30][O:29][N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]1=[O:14])=[O:20]
Reactant: C1CCOC1
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)CON1CCc2ccc([N+](=O)[O-])cc2C1=O
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution consisting of 7-nitro-1,2,3,4-tetrahydroisoquinolin-1-one (2.0 g, 10.4 mmol) in tetrahydrofuran (300 mL) was added sodium hydride (500 mg, 60% suspension in oil, 12.5 mmol). To the resulting mixture was added methyl bromoacetate (1.1 mL, 11 mmol). After 3 hours, ethyl acetate (20 mL) was added followed by water (25 mL). The solution was concentrated and the resulting oil was partitioned between ethyl acetate and water (1:1,200 mL). The layers were separated and the organic layer was washed successively with water (1×100 mL) and brine (1 ×100 mL). The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was treated with ethyl acetate and a solid formed. The solution was filtered to give the title compound (1.6 g, 55% yield).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]1[CH2:8][O:7][CH:6]=[CH:5][CH2:4]1.OOO.[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](C(C)C)[CH:16]=1)(C)C.C1C[O:28]C=CC1.OOO.C(C1C=CC=C(C(C)C)C=1)(C)C>>[C:8]1([CH:3]=[CH:4][CH:5]=[C:6]([OH:7])[CH:12]=1)[OH:1].[C:20]1([CH:15]=[CH:16][C:17]([OH:28])=[CH:18][CH:19]=1)[OH:1]
Reactant: C1=COCCC1
Reactant: CC(C)c1cccc(C(C)C)c1
Reactant: [OH-]
Agent: OOO
Agent: [Na+]
Product: Oc1ccc(O)cc1
Product: Oc1cccc(O)c1
Temperature: 80 °C

Procedure:
One commercial process, believed to be practiced by the Sumitomo Chemical Company, Ltd. is described in part by Suda et al. U.S. Pat. No. 3,953,521, British Patent Specification No. 921,557, Suda et al. U.S. Pat. No. 3,950,431, Suda et al. U.S. Pat. No. 3,923,908, Suda et al. U.S. Pat. No. 3,928,469, and Japanese Pat. No. 61-327 and Japanese Kokai No. 58-88357. The Sumitomo process involves the continuous production of m- and p-DHP by hydroperoxidation of m- and p-DIPB in liquid phase using an alkali catalyst, such as 10-20 vol % of a 2% sodium hydroxide (NaOH) solution at 95°-115° C. and air at a pressure within the range of atmospheric to 10 atmospheres. The hydroperoxidation product is extracted with a 4% aqueous sodium hydroxide solution to separate DHP and m-diisopropylbenzene hydroxyhydroperoxide (HHP) from unreacted m-DIPB and diisopropylbenzene monohydroperoxide (MHP). The MHP/m-DIPB fraction is recycled to the hydroperoxidation reaction vessel. The DHP/HHP fraction, in the form of an aqueous solution containing sodium salts of DHP and HHP, is heated to 80° C. and extracted with methyl isobutyl ketone (MIBK) to recover DHP and HHP. The MIBK solution of DHP/HHP is then washed with an organic solvent to reduce the HHP content, and mixed with an acid catalyst, such as 0.5-2% concentrated sulfuric acid (H2SO4) and, in some instances, hydrogen peroxide (H2O2) to decompose the DHP to either resorcinol or hydroquinone and acetone. The decomposition product is then neutralized with an aqueous ammonia solution, then distilled to obtain crude resorcinol or hydroquinone. Methods for purifying the crude resorcinol are described in Suda et al. U.S. Pat. Nos. 3,929,920; 3,911,030, and 3,969,420, and Japan Kokai No. 78-53626 and British Pat. No. 2,061,926 A.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N:6]=[C:23]=[O:25])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(Cl)cc(F)c(N)c1[N+](=O)[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(F)c(N=C=O)c1[N+](=O)[O-]

Procedure:
4-Chloro-6-fluoro-3-methoxy-2-nitroaniline (0.5 g, 2.27 mmol) was dissolved in anhydrous toluene (30 ml) and triethylamine (0.46 g, 4.54 mmol) was added. This solution was slowly added to a stirred solution of triphosgene (0.67 g, 2.27 mmol) in toluene (30 ml) and the solution refluxed for 2 hr. The solution was cooled and filtered. Clear filtrate was evaporated in vacuo to afford the title compound. 1H NMR (CDCl3, 3.00 MHz) 3.96 (3H, s), 7.38 (1H, d, J=8.8 Hz) ppm.
Reaction SMILES: C(OC(=O)C)(=O)C.C(O)(=O)C.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][CH2:16]2>C1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[Br:12][C:13]1[CH:14]=[C:15]2[C:20]([C:19]([CH3:24])([CH3:23])[CH2:18][CH:17]=[CH:16]2)=[CH:21][CH:22]=1
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC1(C)CC=Cc2cc(Br)ccc21
Reaction time: 1 h

Procedure:
To a cold mixture (0° C.) of 209 g (200 mmol) of chromium trioxide, 100 ml (1.06 mol) of acetic anhydride and 200 ml (3.5 mol) of acetic acid was added a solution of 10 g (41.8 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 125 ml of benzene. The reaction mixture was stirred for 1 hour, quenched with ice cold water and extracted with Et2O (3×100 ml). The organic layer was dried over MgSO4, concentrated in vacuo, and purified by column chromatography (silica, 10% EtOAc-hexane) to give the title compound as a white solid.
Reaction SMILES: I[CH2:2][C:3]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4]1.[C:13]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[C:13]([O:17][C:18]([NH:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4]2)[CH2:25][CH2:26]1)=[O:27])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)C1(CI)CC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(CC2(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 120 °C
Yield: 22.7 %

Procedure:
A mixture of tert-butyl 1-(iodomethyl)cyclopropanecarboxylate (1.9 g 6.7 mmol, step 1 of Example 3), tert-butyl(piperidin-4-ylmethyl)carbamate (3.0 g, 14 mmol), N,N-diisopropylethylamine (5.8 mL, 34 mmol) in N,N-dimethylformamide (25 mL) was heated at 120° C. for 20 h. After cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate/toluene (1:2, 60 mL×2), washed with water (50 mL×2), brine (50 mL), dried over MgSO4, filtered and concentrated to give brown oil. The oil was chromatographed on a column of silica gel eluting with CH2Cl2/methanol (10:1) to give 560 mg (1%) of the title compound as clear brown oil. MS (ESI) m/z: 369 (M+H)+. 1H-NMR (CDCl3) δ: 4.60 (1H, br), 3.08-2.82 (4H, m), 2.59 (2H, s), 2.10-1.90 (2H, m), 1.75-1.55 (4H, m), 1.50-1.05 (23H, m).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[F:10].O[CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH2:14][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH3:12])=[CH:4][C:3]=1[F:10]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Oc1cc(F)c(Br)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1cc(F)c(Br)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
To a solution of 4-bromo-3,5-difluorophenol (5.0 g), tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate (5 g) and triphenylphosphine (7.5 g) in THF (50 mL) was added diisopropyl azodicarboxylate (1.9 M in toluene, 14 mL) dropwise at room temperature. The reaction mixture was stirred at 60° C. overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to afford the title compound (5.1 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7](O)[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(NC(C)C)(C)C.[CH3:33][C:34]([C:36]12[CH2:45][CH:40]3[CH2:41][CH:42]([CH2:44][CH:38]([CH2:39]3)[CH2:37]1)[CH2:43]2)=[O:35]>C1COCC1.CCCCCC>[C:36]12([C:34](=[O:35])[CH2:33][C@H:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH3:8])[CH2:43][CH:42]3[CH2:41][CH:40]([CH2:39][CH:38]([CH2:44]3)[CH2:37]1)[CH2:45]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@@H](O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@H](CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 17 %

Procedure:
The method followed that described in Example 9 but using (+)-(R)-1-(4-pyridyl)ethanol (1.84 g, 15.0 mmol) in THF (80 ml), butyllithium (1.6M; 9.4 ml, 15.0 mmol) in hexane, p-toluenesulfonyl chloride (2.86 g, 15.0 mmol), diisopropylamine (6.31 ml, 45.0 mmol) in THF (120 ml), butyllithium (1.6M; 28.12 ml, 45.0 mmol) in hexane and 1-adamantyl methyl ketone (8.0 g, 45 mmol). Chromatography, on elution with petrol-ether-triethylamine 100:50:1 gave the title compound (722 mg, 17%), which crystallised from hexane, m.p. 48°-49° C.; [α]D -6.6° (c 1.0, MeOH). IR, NMR and MS data were the same as given in Example 14.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[O:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]I)=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][O:22][C:15]3[C:16]([Cl:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[Cl:13])=[CH:27][CH:28]=2)[C:9]#[N:10])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1CC#N
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Product: COc1cc(Br)ccc1C(C#N)Cc1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using (4-bromo-2-methoxyphenyl)acetonitrile (III.4) and 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/Tol 50 to 75%, afforded the desired compound as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)=O.[H-].[Na+]>CS(C)=O.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[NH:18][C:3](=[O:2])[C@H:5]3[N:6]([CH2:7][CH2:8][CH2:9]3)[CH2:10][C:11]=2[CH:16]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ncc(Br)cc2CN2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of (S)-1-(2-amino-5-bromo-pyridin-3-ylmethyl)pyrrolidine-2-carboxylic acid methyl ester (3.66 g, 11.6 mmol) in DMSO (120 mL) was treated with NaH (60% dispersion in mineral oil, 0.47 g, 11.7 mmol). After stirring at room temperature for 4 h, the mixture was diluted with H2O (2500 mL) and extracted with EtOAc (5×150 mL). The combined organic layers were washed with H2O (4×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2,/MeOH, 99:1) gave the title compound (2.75 g, 84%) as an off-white solid: MS (ESI) m/e 282 (M+H)+.
Reaction SMILES: C([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O-:6])=O)C.[C:11]1(P(C2C=CC=CC=2)CC2C(CP(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC=2)[CH:16]=CC=C[CH:12]=1.C=CCCCCCC.[H][H].[C]=O>[Rh].C1(C)C=CC=CC=1>[CH:4](=[O:6])[CH2:3][CH2:7][CH2:8][CH2:9][CH2:10][CH2:12][CH2:11][CH3:16]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: [H][H]
Reactant: c1ccc(P(Cc2ccccc2CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Agent: [Rh]
Agent: [C]=O
Solvent: Cc1ccccc1
Solvent: C=CCCCCCC
Product: CCCCCCCCC=O
Temperature: 105 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A 300-mL stainless steel autoclave equipped with a magnetically driven stirrer was charged under nitrogen with rhodium (14.55 mg of rhodium, 0.14 mmole charged as the 2-ethylhexanoate salt), α,α'-bis(diphenylphosphino)-o-xylene ligand (0.16 gm, 0.34 mmole), 1-octene (22.44 grams), and toluene (70 mL). This was pressured to 300 psig with a 1/1 mixture of hydrogen/carbon monoxide (synthesis gas) and heated to 105° C. The autoclave was repressured to 300 psig with the synthesis gas mixture whenever the pressure dropped to 250 Psig. The reaction was kept at 105° C. for 2 hours, during which time a total pressure drop of 460 psig was observed. The mixture was analyzed by gas/liquid chromatography and showed a 94.3 percent conversion of 1-octene. A 90.6 percent yield to isomeric nonanal products was obtained based on 1-octene charged. The ratio of linear/branched nonanal product was 3.47/1.
Reaction SMILES: CCCCCCCCC/C(/C(O)=O)=C\[C:12]1[C:18](=[O:19])[C:17]([O:20]C)=[C:16]([O:22][CH3:23])[C:14](=O)[C:13]=1[CH3:24].Br[C:29]1C(Br)=C(C)C=C(Br)[C:30]=1[OH:38]>CC1C=C(OC)C(O)=C(OC)C=1OC>[CH3:23][O:22][C:16]1[CH:14]=[C:13]([CH3:24])[CH:12]=[C:18]([O:19][CH3:29])[C:17]=1[OH:20].[CH3:23][O:22][C:16]1[CH:14]=[C:13]([CH3:24])[C:12]([O:38][CH3:30])=[CH:18][C:17]=1[OH:20]
Reactant: CCCCCCCCC/C(=C\C1=C(C)C(=O)C(OC)=C(OC)C1=O)C(=O)O
Reactant: Cc1cc(Br)c(O)c(Br)c1Br
Agent: COc1cc(C)c(OC)c(OC)c1O
Product: COc1cc(C)cc(OC)c1O
Product: COc1cc(O)c(OC)cc1C
Yield: 10 %
Yield: 5 %

Procedure:
The second step in the synthesis of E3330 is the most problematic, where the Ullmann-type methanolysis of 2,3,6-tribromo-4-methylphenol (5) results in multiple reduction byproducts that are not disclosed in the literature.13,14 The optimized Ullmann conditions in our hands result in a mixture of 4-methyl-2,3,6-trimethoxyphenol (11, 75-85%), 2,6-dimethoxy-4-methylphenol (12, 10-15%), and 2,5-dimethoxy-4-methylphenol (13, 5-10%). (Scheme 2) The resulting phenols are alkylated to generate 2,3,4,5-tetramethoxytoluene (6) and the two trimethoxytoluenes (14 and 15). The isolated yield is considerably lower than the observed conversion by NMR, and removal of the two reaction sideproducts is necessary because both lead to E3330 derivatives missing crucial methoxy substituents.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)C>[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:17]([C:15]1[CH:16]=[C:2]([I:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:46]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(I)cc2oc(-c3ccccc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cc(I)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
A mixture of 6-iodo-2-phenylbenzoxazole-4-carboxylic acid (75 mg, 0.21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol), 1-hydroxybenzotriazole (55 mg, 0.41 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (69 mg, 0.25 mmol) in DMF (5 mL) was stirred 10 min at room temperature, then triethylamine (0.10 mL, 0.82 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with diethyl ether (50 mL) and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide) followed by recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-iodo-2-phenylbenzoxazole-4-carboxamide (64 mg, 63%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.91 (br s, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.25-8.20 (m, 2H), 8.06 (d, J=1.5 Hz, 1H), 7.65-7.55 (m, 3H), 4.65-4.52 (m, 1H), 3.32-3.10 (m, 2H), 2.70-2.50 (m, 5H), 2.20-1.20 (m, 2H), 1.65-1.45 (m, 4H), 1.25-1.10 (m, 2H); MS (ESI+) m/z 502 (M+H); HPLC>99% (AUC), tR=13.83 min.
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1)=[NH:7].[ClH:21]>O>[ClH:21].[NH2:7][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1)=[NH:5]
Reactant: COC(=O)c1ccc(NC(=N)N)cc1OC
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: O
Product: COc1cc(NC(=N)N)ccc1C(=O)O
Temperature: 77.5 °C
Reaction time: 3 h
Yield: 93.5 %

Procedure:
Into a reactor was added 5 (29.8 kg, 104 mol) and water (475 L). The mixture was heated to 75 to 80° C. and concentrated HCl (107 kg, 1051 mol) was added over a minimum of 30 min while maintaining the temperature between 75 and 80° C. The reaction mixture was stirred for 3 h at 75 to 80° C. The reaction mixture was sampled and the % conversion was determined by HPLC analysis. The mixture was heated at 75 to 80° C. until the % conversion reached >97.3% or until at total reaction time of 7 h. The reaction was cooled to 20 to 25° C. over a minimum of 3 h and stirred for an additional 2 h at 20 to 25° C. The reaction was filtered and washed with 16% w/w HCl (2×35 kg), water (82 L) and heptane (2×120 L). The resulting wet cake was dried under vacuum at 35 to 50° C. to provide 23.9 kg (93% yield) of 6. 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.72 (s, 4H), 7.69 (d, J=8.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.81 (dd, J=2.3, 8.8 Hz, 1H), 3.80 (s, 3H); MS (ESI) m/z 210.4 (M+, 100%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].ClC1C=[CH:20][C:16]([C:17](N)=O)=[C:15](OC(C)C)N=1.C([N:28](CC)CC)C>C(#N)C>[C:16]([NH:28][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])([CH3:20])([CH3:17])[CH3:15]
Reactant: CC(C)Oc1nc(Cl)ccc1C(N)=O
Reactant: CCN(CC)CC
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)ccc1C(N)=O
Temperature: 80 °C
Yield: 29.6 %

Procedure:
To a solution of 2,6-dichloro-nicotinamide (1) (4 g, 20.9 mmol) in acetonitrile (anhydrous, 60 mL) were added tert-butylamine (2) (13.28 mL, 12.6 mmol) and triethylamine (15.7 mL, 12.6 mmol). The reaction was heated at 80° C. for 2 days. The solution was cooled to room temperature and the resulting suspension was filtered. The filtrate was concentrated in vacuo. The residue was purified by Biotage silica gel chromatography with 20%-100% EtOAc/hexanes gradient elution to afford 850 mg (18% yield) of the title compound.